Influenza is a persisting global threat, and the most pressing unmet need is to improve vaccination strategies to be more effective, with this fundamentally hinging on a better understanding of vaccinemediated immunity in humans. Due to the ubiquitous nature of influenza, people are exposed to influenza virus at an early age, resulting in the early development of antibody responses to the first encountered influenza strains. From this initial exposure to influenza via infection or vaccination, the initial influenza antibody repertoire is established, and it is constantly reshaped during one?s lifetime. Recent studies have suggested that this initial antibody repertoire generated from the first exposure is ?imprinted? in the immune system and exerts a major influence on the nature of the antibody response elicited upon subsequent challenges. Such imprinting sets the immune system on a path that bias immune responses to subsequent exposures to influenza, and there is an increasing understanding that early childhood imprinting might be the reason for the limited effectiveness of the annual flu vaccination. This study aims to characterize the immune response to influenza in young children and its effect on subsequent responses to influenza vaccination. The hypothesis is that that the first exposure through infection results in stronger imprinting of initial influenza antibody repertoire than the first exposure through vaccination. In Aim 1, the immune response to influenza vaccine in children who had documented prior natural infection or documented prior vaccination will be compared, focusing on the persistence of the antibodies from the first time point over 2 years of subsequent vaccinations. In Aim 2, the antibodies comprising the imprinted antibody repertoire will be functionally characterized to better understand the features of the imprinted antibodies. Collectively, this study will potentially elucidate the rules and mechanisms governing imprinting, which can be leveraged into the development of better vaccine immunogens as well as vaccination strategies.